The goal of this revised program project is to delineate the etiopathogenesis of rheumatoid arthritis (RA), and to use this information to devise new means for prevention and treatment of the illness. Accumulated evidence suggests that there is no single cause of RA. Instead, the disease is probably the final outcome of (i) multiple independent disease susceptibility genes, (ii) developmental differences in the immune system that are not necessarily under direct genetic control, (iii) repeated exposure to triggering antigens in the environment, (iv) a failure to control the cytokine networks that perpetuate joint inflammation. No animal model adequately reproduces this constellation of factors. Therefore, to understand the etiopathogenesis of RA requires a collaborative team of scientists, that can utilize state of the art technology in molecular and cellular biology to study well characterized RA patient material. This is the strategy for achieving the long term goal of the program project. Specifically, the revised program includes four research projects and two cores. Project 1 concerns how immunoglobulin, HLA, and T cell receptor genes interact to increase RA susceptibility; Project 2 focuses on developmental changes in the function of antigen-presenting B cells that may predispose to, and perpetuate, RA; Project 3 deals with the RA disease susceptibility region on HLA molecules, and how it affects immune responses to environmental antigens that may trigger arthritis; Project 4 is based upon the hypothesis that a defect in monocyte deactivation may inhibit the resolution of synovitis in patients who develop RA. Each project uses patient material that is supplied by a Sample Acquitision Core. The experimental procedures exploit techniques in molecular and cellular biology that have not heretofore been used effectively to study RA.